Emanuele Spina

Gender differences in non-motor symptoms in early Parkinson's disease: A 2-years follow-up study on previously untreated patients

BACKGROUND We recently showed specific sex-related patterns of non motor symptoms (NMS) in early, drug-naïve PD patients. However, to date studies investigating gender-related effects of dopaminergic treatment on NMS in early PD are lacking. METHODS In the present study, we first report a prospective assessment of gender-related differences in the spectrum of NMS before (baseline) and after starting dopaminergic therapy (2-year follow-up) in a large cohort of newly diagnosed PD patients. Differences in NMS frequency between baseline and follow-up were evaluated by McNemar test. Spearmans rank test was employed to explore interactions between NMS and drug treatment. RESULTS One-hundred and thirty four PD patients (86M and 48W) were included in the present study. At 2-year follow-up, Sadness/blues presented a significant percentage reduction as compared to baseline in both sexes, while Urgency, Daytime sleepiness, Weight change and Sex drive presented a significant percentage increase only in men. At follow up men complained of a greater number of NMS as compared to women. Occurrence of Weight change was related to therapy in both sexes. Male gender was found to be a risk factor for developing Dribbling and Nocturia, irrespective of therapy and clinical features. CONCLUSIONS In conclusion, our study showed that mood symptoms improved after the introduction of therapy in both sexes, while men appeared to be more prone to develop some NMS possibly linked to dopaminergic treatment.

A Four-Year Longitudinal Study on Restless Legs Syndrome in Parkinson Disease.

STUDY OBJECTIVES Restless legs syndrome (RLS) prevalence estimates range from 0% to 52% in Parkinson disease (PD), but the causal relationship between the two disorders is still debated. The present study aims to evaluate RLS prevalence in de novo PD subjects, its incidence during the first 4 years from diagnosis, and possible relationships with clinical, laboratory, and neuroradiological data. METHODS One hundred nine newly diagnosed, drug-naïve PD subjects were evaluated at the time of PD diagnosis, and after 2- and 4-years. RLS diagnosis was performed with the RLS Diagnostic Index at each visit. Motor features, additional non-motor symptoms (NMS), and concomitant dopaminergic and nondopaminergic treatments were also gathered. Moreover, at baseline, 65 subjects were randomly selected to undergo a FP-CIT SPECT to study dopamine transporter availability. RESULTS RLS prevalence rose from 4.6% at baseline evaluation to 6.5% after 2 years and to 16.3% after 4 years (P = 0.007). A multinomial logistic stepwise regression model selected NMS Questionnaire items more likely to be associated with RLS at diagnosis (insomnia, OR = 15.555; P = 0.040) and with occurrence of RLS during follow-up (dizziness, OR = 1.153; P = 0.022; and daytime sleepiness; OR = 9.557; P = 0.001), as compared to patients without RLS. Older age was more likely associated to increased RLS occurrence during follow-up in a random effect logistic regression model (OR = 1.187; P = 0.036). A multinomial logistic stepwise model found increased dopaminergic transporter availability of affected caudate and putamen to be more likely associated with RLS presence at diagnosis (n = 5; OR = 75.711; P = 0.077), and RLS occurrence during follow-up (n = 16; OR = 12.004; P = 0.059), respectively, as compared to patients without RLS (n = 88). CONCLUSIONS RLS is present since PD diagnosis, and increases in prevalence during the course of PD. PD subjects with RLS have higher age at PD onset, more preserved dopaminergic pathways, and worse sleep and cardiovascular disturbances.

Is serum uric acid related to non-motor symptoms in de-novo Parkinson's disease patients?

BACKGROUND Low serum uric acid (UA) has been consistently shown to be associated with increased risk of Parkinsons disease (PD), and to predict faster motor and cognitive decline in established PD. The aim of the present study is to evaluate the relationship between serum UA and non-motor symptoms (NMS) in de novo PD. METHODS Serum UA was measured in consecutively recruited, early drug-naïve PD patients. Exclusion criteria were: treatment with UA modifying drugs; current smoking status; metabolic or cardiac morbidity. All patients completed the NMS Questionnaire (NMSQuest). The relationship between UA levels and NMSQuest domains was explored by logistic regression, subsequently adjusted for age, gender, disease duration (months since reported motor onset) UPDRS part III, H&Y scale, and MMSE. Regression analysis studied the overall relationship between UA levels and total NMS score, and was subsequently adjusted for age, gender, disease duration UPDRS part III, H&Y scale and MMSE. RESULTS Eighty PD patients were recruited. At logistic regression, higher UA levels were related to lower involvement of Attention/Memory (p = 0.004), Cardiovascular (0.009) and Sleep (p = 0.028) domains of NMSQuest. UA levels showed a significant negative correlation with total NMSQuest score at regression analysis (p = 0.001; Adjusted R-squared = 0.319). DISCUSSION The present study investigated, for the first time, the relationship between NMSQuest and UA in de novo PD. Lower UA was related to higher NMSQuest total score and in particular to Attention/Memory, Cardiovascular and Sleep domains. Thus, UA seems to be a major candidate to be a valuable biomarker of such early features of PD as NMS.

Biomarkers of Parkinson's disease: recent insights, current challenges, and future prospects

A biomarker represents a tool possibly helping physicians in predicting onset, diagnosis, and progression of a disease as well as evaluating the response to disease-modifying treatments. Currently, there is no biomarker fulfilling all such ideal criteria for Parkinsons disease (PD). In this article, we have critically reviewed the literature searching for the most reliable and reproducible clinical, biochemical, and imaging biomarkers for prodromal phase, diagnosis, and progression of PD. Different comprehensive batteries of biomarkers have been proposed as a sensitive approach to predict the onset of PD during the prodromal phase. There is a discussion about the redefinition of the clinical diagnosis of PD, including clinical biomarkers as non-motor symptoms; however, on the other hand, we have also observed that imaging biomarkers support the differential diagnosis from other causes of parkinsonism. Various clinical (eg, freezing of gait or cognitive impairment), biochemical (eg, epidermal growth factor, insulin-like growth factor 1, uric acid, etc), and imaging (eg, functional mag- netic resonance imaging, voxel-based morphometry, etc) biomarkers may help envisaging disease progression of PD. To conclude, given the lack of a single biomarker that could track the entire course of the disease, our challenge is to find the best combinations of biomarkers for the different stages of the disease.

Music Therapy for Motor and Nonmotor Symptoms of Parkinson's Disease: A Prospective, Randomized, Controlled, Single-Blinded Study.

aid in the prevention and treatment of osteoporosis. Shuttlecock, consisting of running, kicking, jumping, and swiveling body movements, is mainly an exercise of the lower limbs. Shuttlecock kicking is a kind of moderateimpact exercise that stimulates bone formation and conversion, especially in the legs and feet. In the present investigation, data analysis indicated that BMD at the FN, TR, Wd, LC, and RC improved significantly more in the shuttlecock group than in controls after a 6-month intervention (Table 1). In accordance with the current findings, it has previously been shown that playing shuttlecock improves the BMD of postmenopausal women. In postmenopausal women, changes in hormonal balance, particularly declining estrogen levels, and reductions in activity result in reduced muscle strength and BMD. Exercise not only increases serum estradiol levels but also affects the expression of hormones that play critical roles in bone remodeling, such as calcitonin, BGP, and parathyroid hormone. Exercise also inhibits the expression of IL-1, IL-6, and cyclooxygenase-2 to decrease osteoclastogenesis and bone resorption. In the current study, data analysis indicated that calcium, testosterone, and estradiol increased and that bone gla protein and IL-6 decreased significantly more in the shuttlecock group than in controls after a 6-month intervention (Table 1). The current study indicates that playing shuttlecock resulted in significantly greater improvements in Berg Balance Scale score in the shuttlecock group than in controls after a 6-month intervention (Table 1). These findings showed a trend toward better balance performance in postmenopausal women after playing shuttlecock. Comparison of results from the current study with previously reported results shows that playing shuttlecock may improve estrogen levels, bone metabolism index, and postural balance, thereby ultimately reducing the risk of falls in postmenopausal women. The results of this study recommend that playing shuttlecock may increase BMD, calcium, testosterone, estradiol, and BBS score and reduce BGP and IL-6 levels of postmenopausal women. These findings can contribute to the future planning of community-based exercise programs for postmenopausal women.

Validation of an Italian version of the 40‐item University of Pennsylvania Smell Identification Test that is physician administered: Our experience on one hundred and thirty‐eight healthy subjects

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Motor performance deterioration accelerates after 50 years of age in Charcot‐Marie‐Tooth type 1a patients

The aim of our study was to describe, by a case‐control and cross‐sectional design, the correlation between clinical impairment and age in Charcot‐Marie‐Tooth type 1A (CMT1A) patients.

Teaching Video NeuroImages: Finger clonus When the pupil surpassed his master

A 75-year-old man was admitted because of finger tremor. During neurologic examination, bilateral finger clonus was evoked (video on the Neurology® Web site at Neurology.org), and a cervical spinal cord hyperintensity was found (figure).

Bilirubin and Uric Acid: Two Different Anti-oxidants in Parkinson’s Disease

We found the recent paper by Qin and colleagues evaluating uric acid (UA) and bilirubin in Parkinson’s disease (PD) of great interest [1]. Both compounds are powerful endogenous anti-oxidants and, considering the relevance of oxidative stress in PD pathogenesis, they are possibly markers indicating the risk of PD and of its progression. On the one hand, UA, the end-product of purine metabolism, has antioxidant and iron scavenger features, possibly providing natural neuroprotection against PD and other neurological disorders, since both oxidative damage and accumulation of un-sequestered iron have been suggested to take part in neurodegenerative processes [1–6]. Accordingly, UA has been widely demonstrated to be reduced in PD, as also shown by Qin and colleagues [1]. Moreover, lower UA levels indicate an increased risk of developing PD in healthy subjects, and worse motor, nonmotor and radiological outcomes in PD patients [2–4]. On the other hand, bilirubin has not been fully investigated in PD. However, it is well known that plasma total bilirubin is mainly related to heme-oxygenase (HO) [7, 8]. This pathway is activated early in dopaminergic cells exposed to oxidative stress and, notably, in PD patients where cytoplasmatic Lewy bodies displayed intense peripheral HO staining [8]. In line with this, Scigliano and colleagues previously reported increased total bilirubin levels in PD [9], and, accordingly, we recently showed a similar result in our population of newly diagnosed, drug naı̈ve PD subjects [10]. Therefore, it can be hypothesized that HO up-regulation within the substantia nigra is an adaptive response to increased oxidative stress occurring in PD, and is likely to be responsible for systemic bilirubin increase [7, 8, 10]. We also found PD subjects with higher bilirubin levels presenting worse motor outcomes at baseline visit, but better ones after two-year follow-up [10]. As a consequence, higher bilirubin levels might depict a more pronounced neurodegenerative process, but are possibly related to improved health outcomes over time [7, 8, 10]. Intriguingly, although Qin and colleagues reported higher direct bilirubin and lower indirect bilirubin levels in PD patients, as compared to controls, no difference in total bilirubin concentrations was found [1]. This result is not in line with previous studies [9, 10], and can be explained by the presence of confounding factors affecting bilirubin levels and/or by bilirubin variations during the course of the disease. Among possible confounding factors, for instance, we must report the presence of HO polymorphisms, possibly modifying bilirubin levels in PD cohorts with different genetic backgrounds [11]. The latter might be particularly relevant since Qin and colleagues described a Chinese population, whereas all previous similar studies have been conducted in Caucasians [9, 10]. In addition, there are several comorbidities affecting bilirubin that are difficult to exclude completely in clinical practice [10]. As an additional hypothesis, bilirubin levels might also change & Carmine Vitale cavit69@hotmail.com

Comment on Numao et al.: Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson's disease, multiple system atrophy and progressive supranuclear palsy

We read with great interest the recently published paper “Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy” by Numao and colleagues [1]. The authors described different correlation patterns between serum Insulin like-Growth Factor 1 (IGF-1) and clinical parameters in Parkinson’s disease (PD) and Multiple System Atrophy (MSA). In fact, as regards PD they found that serum IGF-1 levels decrease as the disease progresses, whereas in MSA serum IGF-1 levels increase as disease worsens. Thus, after discussing previous studies on the same topics [2,4,5], they concluded that this different profile of IGF-1 among PD and MSA may reflect different ongoing disease processes. However, in our opinion some important points need to be considered. As regards PD, they found that only the early PD group presented higher serum IGF-1 levels as compared to controls. Moreover, considering the entire PD cohort, patients with H&Y stage 2 presented significantly higher serum IGF-1 levels as compared to patients with H&Y stages 3e5. These results support previous evidence suggesting that IGF-1 is an early biomarker of PD [2,4,5]. On the other hand, in contrast to our previous study [2], they found no correlation between IGF-1 levels and UPDRS-III score when considering only the early PD and drug-naïve PD cohorts (8 and 25 patients, respectively) and an inverse correlation when considering the whole PD cohort (79 patients). They concluded that these findings support the hypothesis that a compensatory increase in serum IGF-1 occurs to counteract the degeneration of dopaminergic neurons in the early phase of PD and that the neuroprotective capacity decreases later during the course of the disease. We would like to suggest that caution is required in generalizing their findings. In fact, our previous prospective study enrolling 37 early, drug-naive PD patients suggests that serum IGF-1 levels at diagnosis are related to the UPDRS-III